There are diseases caused by abnormality of estrogen or progesterone as organic gynecological diseases. Examples of the diseases include endometriosis, uterine fibroids, and uterus adenomyosis.
As treatment of such diseases, administration of gonadotropin agonist (GnRH agonist), as a drug therapy, is known, however, a period for drug administration is restricted because of the side effects such as bone mineral loss and ovarian dysfunction symptoms, thus no gynecological disease therapeutic agents for long-term use have existed yet, and so surgical therapy such as surgical resection is still a first choice.
Therefore, for the treatment of gynecological disease, a drug effective for long-term administration to inhibit the growth of ectopic endometrial tissue and suppress or improve the intra-uterine fibroids and uterus adenomyosis has been desired. It has also been desired to relief pains such as lower abdominal pain and low back pain caused by these gynecological diseases.
Conventionally, as a drug to inhibit binding of estrogen to the receptor antagonist, tamoxifen (Registered Trademark: Nolvadex) with an indication of breast cancer has been used since the 1980s in Japan. However, it is reported that this drug causes uterine body cancer, uterine sarcoma or endometriosis, thus it may not be used to treat estrogen-dependent diseases including endometriosis. The mechanism of proliferative effects of the drug against the endometrium is caused by its endogenous partial agonistic action to the estrogen receptor.
Then, fulvestrant (Registered Trademark: Faslodex) was approved as a therapeutic agent for postmenopausal breast cancer. This drug, unlike tamoxifen, does not provide endogenous partial agonist action to the estrogen receptor. However, this drug has low gastrointestinal absorption rate as well as short half-life even when intravenously administrating, thus a high capacity intramuscularly administration is necessary, and thus the dosage form is intramuscular injection. Therefore, it will never be used orally for treating estrogen-dependent diseases.
Further, as a selective estrogen receptor modulator (hereinafter, sometimes abbreviated as “SERM”), raloxifene (Registered Trademark: Evista) has been approved with an indication for osteoporosis treatment. However, this drug is an osteoporosis therapeutic agent having a bone mass-increasing by estrogen receptor partial agonist activity, thus it will never be used for treating estrogen-dependent diseases, that is gynecological diseases caused by ectopic endometrial tissue growth such as endometriosis, uterine fibroids, and uterus adenomyosis.
Other selective estrogen receptor modulators, (7α)-21-[4-[(diethylamino) methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-triene-3-ol or a pharmaceutically acceptable salt thereof, which have been developed as a breast cancer therapeutic agent, are known (see Patent documents 1 and 2).